"Coreceptor switching" is the evolution of the HIV-1 envelope from exclusive use of CCR5 for viral entry to alternative use of CCR5 or CXCR4 and finally to exclusive use of CXCR4. Viruses that can use CXCR4 as a coreceptor have an expanded target cell range and cause more rapid disease progression. Coreceptor switching occurs at different rates in different patients, and may not occur at all. The potential use of CCR5 inhibitors for antiviral therapy may substantially increase the rate of coreceptor switching. The goal of this proposal is to define the viral and host determinants that influence the rate of coreceptor switching. Viral determinants of coreceptor switching to be investigated include relative avidity for CCR5, fitness of "transitional state" viruses undergoing coreceptor change, binding to CXCR4 without functional use of the coreceptor, and efficiency of clade C versus clade B viruses viruses in coreceptor switching assays in vitro and in hu-PBL-SCID mice. Host factors to be investigated include CCR2, CCR5, and IL-4 promoter polymorphisms, relative numbers of Thl versus Th2 CD4 T cells, IL-4 and IL-12 cytokine levels, and relative numbers of memory effector versus central memory CD4 T cells. The information gained will be important for understanding disease progression and the safety of coreceptor inhibitors. [unreadable] [unreadable]